1. Field of the Invention
The present invention relates to novel compounds having retinoid-like activity. More specifically, the present invention relates to compounds having an oxiranyl phenyl carboxylic acid portion and a second portion which is a substituted or unsubstituted chromanyl, thiochromanyl or tetrahydroquinolinyl group. The acid function may also be converted to an alcohol, aldehyde or ketone or derivatives thereof, or may be reduced to --CH.sub.3.
2. Background Art
Compounds which have retinoid like activity are well known in the art, and are described in numerous United States and foreign patents and in scientific publications. It is generally known and accepted in the art that retinoid like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and preventing malignant hyperproliferative diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer and myeloid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointimal hyperproliferation, for treating and preventing other non-malignant hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative vitreal retinopathy and dysplasias, for treating autoimmune diseases and immunological disorders (e.g. lupus erythematosus) for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases associated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for treating dry eye syndrome and for reversing and preventing the effects of sun damage to skin.
European Patent EP 170 105 A discloses certain new para substituted 4-oxiranyl benzoic acids and their esters and amides having anti-cancer and anti-leukemia activity. The compounds are said to induce differentiation of pre-malignant and malignant cells, and therefore may serve in the therapy of pre-malignant and malignant diseases of humans and animals. An example of the compounds of this disclosure is benzoic acid, 4-[3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)oxira nyl-, trans-.
The article "Retinobenzoic acids. 3. Structure-Activity Relationships of retinoidal Azobenzene-4-carboxylic acids and Stilbene-4-carboxylic acids" by H. Kagechika et al., Journal of Medicinal Chemistry, 1989, 32, pp 1098-1108 discloses oxirans substituted with a 4-(carboxy)phenyl group and with 5,5,8,8-tetramethyltetrahydronaphthyl group.
U.S. Pat. No. 4,826,984 describes ethylene compounds substituted with a chromanyl or thiochromanyl group and with a substituted phenyl group as anticancer agents. Specific examples of this reference are ethyl (E)-p-[2-(4,-dimethylthiochroman-6-yl)propenyl]benzoate, and (E)-p-[2-(4,-dimethylthiochroman-6-yl)propenyl]benzoate.
Published German patent application DE 3316932 A1 also describes ethylene compounds substituted with a chromanyl or thiochromanyl group and with a substituted phenyl group. The compounds are described as active against acne, psoriasis and other dermatological disorders. Published European patent application Nos. 0 130 795 and 0 350 846 describe similar compounds.
International Application published under the Patent Cooperation Treaty WO 85/00806 describes ethylene compounds substituted with a chromanyl or thiochromanyl group and with a substituted heteroaryl group (such as pyridyl, pyrimidinyl and thienyl) as retinoid analogs.
Several co-pending applications and recently issued patents of the present inventor, which are assigned to the assignee of the present application, are directed to further compounds having retinoid like activity. One of said patents, U.S. Pat. No. 5,324,840, describes 2,2,4,4-tetramethyl-chroman-6-yl and phenyl substituted ethene derivatives where the chroman group also bears a substituent (such as an alkyl group) in the 7-position. Tetrahydronaphthyl and heteroaryl substituted ethene derivatives are further described in published European application EPO 0 098591, 0 253 302, and in published international application WO 92/06948.